This proposal is aimed to establish and to evaluate the potential significance of our preliminary laboratory findings that naturally occurring non-radioactive isotopes of lithium, namely Li-6 and Li-7, which together comprise commercially available Li (natural lithium, Li-N), are handled differentially by many biological systems (i.e., isotope effects). To characterize differential mobility of each Li isotope across cell membrane, RBCs from rats and cats will be utilized in vitro and in vivo. In vitro RBC uptake and efflux will be studied in the presence and absence of selective transport inhibitors to further characterize differential effects. This isotope effect will be studied directly on a simple neuronal structure, namely on isolated frog sympathetic ganglia preparation as a model, to support the idea that this important phenomenon also occurs in neuronal structures. Thorough comparative pharmacokinetics of Li isotopes and the natural Li will be studied through investigation of gastrointestinal absorption, distribution into plasma and RBC (and CSF on some occasions), relative peak plasma levels, plasma and tissue biological halflives in both acutely and chronically treated mice and cats. Correlative to the pharmacokinetic studies, a selective comparative pharmacology-toxicology of Li isotopes and Li-N will be studied. Behavioral, electroencephalographic and toxicologic (primarily LD50, gross behavioral, and nephrotoxicology) alterations produced by each Li isotope and Li-N will be quantitatively measured in vivo in cats and mice, to evaluate the relative effects of each isotope and of Li-N in whole animals. Thus the potential clinical importance of Li-6 as a minor contaminant in Li-N during chronic Li therapy will be evaluated.